The present invention relates to a benzoxazole compound which selectively activates, among peroxisome proliferator-activated receptors (PPARs), PPARxcex1, and is usefully employed as a drug for preventing and/or treating diseases including hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases. The invention also relates to a pharmaceutical composition containing the compound.
PPARs are known to be a family of nuclear receptors, and three sub-types thereof (xcex1, xcex3, xcex4) have been already identified (Nature, 347, 645-650, 1990; Cell, 68, pp. 879-887, 1992; Cell, 97, pp. 161-163, 1999; Biochim. Biophys. Acta., 1302, pp. 93-109, 1996; and Journal of Medicinal Chemistry, 43, pp. 527-550, 2000).
Among the three sub-types, PPARxcex1 is expressed predominantly in the liver and is known to be activated by a plasticizer or a fibrate-type drug such as Wy 14643 or a commercially available pharmaceutical; e.g., clofibrate, fenofibrate, bezafibrate, or gemfibrosil (Journal of the National Cancer Institute, 90, 1702-1709, 1998, Current Opinion in Lipidology, 10, pp. 245-257, 1999).
In mammals, activation of PPARxcex1 is known to promote xcex2 oxidation of fatty acids and lower a blood triglyceride level. In humans, the total level of blood lipids including low-density lipoprotein (LDL) cholesterol and very low-density lipoprotein (VLDL) cholesterol decreases. Thus, a PPARxcex1-activator is useful as a drug for preventing and/or treating a disease such as hyperlipidemia. In addition, the PPARxcex1-activator, which increases the high-density lipoprotein (HDL) cholesterol level and, in blood vessels, suppresses expression of VCAM-1 (a type of cell adhesion molecules), is considered to be usefully employed as a drug for preventing and/or treating diseases such as arteriosclerosis. Furthermore, the PPARxcex1-activator is considered to be usefully employed as a drug for preventing and/or treating diseases such as diabetes, inflammatory disease, and heart diseases (Journal of Atherosclerosis and Thrombosis, 3, pp. 81-89, 1996; Current Pharmaceutical Design, 3, pp. 1-14, 1997, Current Opinion in Lipidology, 10, pp. 151-159, 1999; Current Opinion in Lipidology, 10, pp. 245-257, 1999; The Lancet, 354, pp. 141-148, 1999; Journal of Medicinal Chemistry, 43, pp. 527-550, 2000; and Journal of Cardiovascular Risk, 8, pp. 195-201, 2001).
PPARxcex3, which is expressed predominantly in adipocytes, is known to play an important role in differentiating and proliferating adipocyte. Examples of known activators for PPARxcex3 include thiazolidine derivative drugs such as troglitazone, pioglitazone, and rosiglitazone. These drugs are known to transform fully differentiated adipocytes having reduced insulin sensitivity into small adipocytes having high insulin sensitivity, thereby improving insulin resistance (Journal of Biological Chemistry, 270, 12953-12956, 1995; Endocrinology, 137, pp. 4189-4195, 1996; Trends Endocrinol. Metab., 10, pp. 9-13, 1999; and J. Clin. Invest., 101, pp. 1354-1361, 1998). However, PPARxcex3 has been reported to have the adverse effects on humans of increasing the amount of fat and body weight and causing obesity (The Lancet, 349, pp. 952, 1997). Recently, it is also reported that a PPARxcex3 antagonist possibly improves insulin resistance (Proc. Natl. Acad. Sci., 96, pp. 6102-6106, 1999; The Journal of Biological Chemistry, 275, pp. 1873-1877, 2000; and J. Clin. Invest., 108, 1001-1013, 2001).
PPARxcex4, which is present ubiquitously in the body, is known to take part in lipid metabolism. However, only a few high-selectivity PPARxcex4 activators have been reported, and the biological meaning of PPARxcex4 remains unclear. At present, the structures of PPARxcex4 activators are reported in a wide range of literature (Diabetes, 46, 1319-1327, 1997; and Journal of Medicinal Chemistry, 43, pp. 527-550, 2000). In a recent report, GW 501516, a type of PPARxcex4 activator, elevates HDL level in monkeys (Proc. Natl. Acad. Sci., 98, pp. 5306-5311, 2001). However, a compound F, a PPARxcex4 activator, disclosed in WO 97/28149 exerts an unfavorable effect of accumulating lipids in human macrophages (Journal of Biological Chemistry, 276, pp. 44258-44265, 2001). In addition, results of an experiment employing PPARxcex4-deficient mice indicate that activation of PPARxcex4 induces lipid accumulation action (Proc. Natl. Acad. Sci., 99, pp. 303-308, 2002). These phenomena accelerate arteriosclerosis and reduce the effect of treating arteriosclerosis. Therefore, effects of PPARxcex4 on treatment of arteriosclerosis remain unelucidated.
As described above, a PPARxcex1-selective activator having low activity to PPARxcex3 and to PPARxcex4 is expected to be useful for preventing and/or treating, without accompanying obesity or increase in body weight, diseases such as hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases.
WO 94/01420 discloses the following compounds having a benzoxazole skeleton (Bioorg. Med. Chem. Lett., 6, pp. 2121-2126, 1996; and Bioorg. Med. Chem. Lett., 6, pp. 2127-2130, 1996) 
WO 96/04260 discloses the following compounds (J. Pharmacol. Exp. Ther., 284, pp. 751-759, 1998). 
WO 97/25042 and WO 97/31907 also disclose compounds having a benzoxazole moiety. However, these compounds do not exhibit PPARxcex1-selective activation effect, but rather exert a strong PPARxcex3 activation effect.
WO 02/46176 discloses compounds represented by the following formula: 
(wherein each of R1 and R2 represents a hydrogen atom, a halogen atom, a nitro group, a C1 to C8 alkyl group, a C1 to C8 alkoxy group, or a C6 to C10 aryl group, or R1 and R2, together with the carbon atoms to which they are attached, may form a benzene ring; X represents an oxygen atom, a sulfur atom, xe2x80x94NR0xe2x80x94 (R0 represents a hydrogen atom or a C1 to C8 alkyl group), or xe2x80x94CHxe2x95x90CHxe2x80x94; G represents a single bond or a carbonyl group; R3 represents a C1 to C8 alkyl group, a C2 to C8 alkenyl group, a C2 to C8 alkyl group, a C3 to C7 cycloalkyl group, a C1 to C8 alkyl group substituted by a C3 to C7 cycloalkyl group, a C6 to C10 aryl group, an arylalkyl group (formed of a C6 to C10 aryl moiety and a C1 to C8 alkyl moiety), a heterocyclic group, or a heterocyclicalkyl group (containing a C1 to C8 alkyl moiety); n is an integer of 0 to 5; Y represents xe2x80x94CH2xe2x80x94, a carbonyl group, or xe2x80x94CHxe2x95x90CHxe2x80x94; Z represents an oxygen atom or a sulfur atom; p represents an integer of 0 to 5; each of R4 and R5 represents a hydrogen atom or a C1 to C8 alkyl group; and W represents a carboxyl group, a C2 to C8 alkoxycarbonyl group, a sulfonic acid group, a phosphonic acid group, a cyano group, or a tetrazolyl group).
However, WO 02/46176 provides a specific description only in terms of thiazole compounds (X in the above formula is a sulfur atom), and no specific description is provided in terms of benzoxazole compounds. The specification discloses activation effect on each sub-type of PPARs. The disclosed compounds activate all sub-types of PPARxcex1, PPARxcex3, and PPARxcex4, and thus are not regarded as PPARxcex1-selective activators.
The present inventors have carried out extensive studies in order to find a compound which selectively activates PPARxcex1 among other PPARs, and have found that a benzoxazole compound represented by the following formula (1) selectively activates PPARxcex1 and is useful as a drug for preventing and/or treating, without accompanying obesity or increase in body weight, diseases including hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases. The present invention has been accomplished on the basis of this finding.
Accordingly, the present invention provides a benzoxazole compound represented by the following formula (1): 
(wherein R1 represents a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C3-7 cycloalkyl group, a C3-7 cycloalkyl-C1-8 alkyl group, a C6-10 aryl-C1-8 alkyl group (the C6-10 aryl moiety may have one or two substituents selected from a halogen atom, a hydroxyl group, a nitro group, an amino group, a di-C1-4 alkylamino group, a C1-4 alkyl group, a C1-4 alkoxy group, a benzyloxy group, a phenylsulfonylmethyl group, and a C1-4 alkanesulfonyloxy group), a pyridyl-C1-8 alkyl group, a C1-8 alkoxycarbonyl-C1-8 alkyl group, or a carboxy-C1-8 alkyl group; R2 and R3 may be the same or different and represent a hydrogen atom, a methyl group, or an ethyl group; and n represents a number of 1 to 3) or a salt thereof.
The present invention also provides a pharmaceutical composition containing a benzoxazole compound represented by the above formula (1) or a salt thereof and a pharmaceutically acceptable carrier.
The present invention also provides a drug containing, as an active ingredient, a compound represented by the above formula (1) or a salt thereof.
The present invention also provides a use, for producing a drug, of a compound represented by the above formula (1) or a salt thereof.
The present invention also provides a method for treating a disease selected from hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases, the method being characterized by administering a compound represented by the above formula (1) or a salt thereof in an effective amount.